Making Tumors More Sensitive to Chemotherapy

Making Tumors More Sensitive to Chemotherapy

Killing cancer: The four descending images reveal how small pieces of RNA (shown in green) designed to reverse a tumor’s resistance to chemotherapy accumulate in a cancer cell over the space of 24 hours. Red dye marks the cell membrane of the cancer cell. Cellular structures called lysosomes (shown in blue) open up the empty bacterial cells that carry the RNA, releasing the RNA into the cell.

Empty bacterial cells can deliver key anti-tumor substances with high precision, new research suggests.

The technique enabled mice to survive aggressive colon, breast, and uterine tumors that killed control animals, a team of researchers report in Nature Biotechnology. In addition, the precision of the antibody-guided delivery system meant that relatively tiny amounts of toxic chemotherapy–up to 3,000 times less than standard therapeutic doses–were effective.

Scientists first used the delivery system to disable the mechanism that drug-resistant tumor cells employ to expel cancer-killing drugs as fast as they are taken up. Then, with the tumors vulnerable to chemotherapy agents once more, a second wave of “minicells”–engineered to carry antibodies that lock on to cancer cells–was used to deliver cancer-killing drugs.

The approach could help overcome the problem of resistance to cancer drugs. Genetic changes in rapidly dividing and mutating tumor cells allow them to eventually shrug off drugs that are initially effective.

Mutations that affect a tumor cell’s ability to metabolize, take up, or, more commonly, pump out cancer drugs lie behind resistance. Very often, drug-resistant cells produce unusually large amounts of P-glycoprotein, a component of the protein pumps that allow cells to expel a range of drugs, including chemotherapy agents, before they can kill the cell.

With this in mind, a team from the biotech firm EnGeneIC, in New South Wales and the University of New South Wales, in Australia, and the Cold Spring Harbor Laboratory, in New York, created minicells–bacteria emptied of their DNA–with the intention of using them to knock out these protein pumps and reverse drug resistance.

To disable the pumps, scientists placed small strands of RNA, called siRNA (small interfering RNA), designed to block expression of the gene responsible for P-glycoprotein, in the minicells. They also attached antibodies to the surface of the minicells that enabled them to stick specifically to cell markers found only on the tumor cells that they were seeking to treat. The minicells were then delivered by intravenous injection.

Once attached to their targets by the antibodies, the minicells were absorbed and quickly released their contents into the tumors of immunologically weakened mice. These animals had received grafts of very aggressive forms of either breast, uterine, or colon cancer.

For all three types of cancer, mice that received chemotherapy delivered by minicells were still alive after 100 days, while mice that received chemotherapy via standard IV infusion died. The researchers speculate that the survival of the minicell-treated mice was due to the highly specific targeting of the toxic chemotherapy. Not only was the treatment more effective, but in mice treated for bowel cancer, the amount of the highly toxic drug used was 3,000 times less than that infused in the control animals.

The research “provides compelling evidence that this strategy inhibits the growth of drug-resistant tumors,” says Daniel Anderson of MIT’s David Koch Institute for Integrated Cancer Research. But he notes that a much more detailed analysis of minicells’ potential interaction with the immune system will be needed before the technique finds its way into the clinic. (The animals in the study did not appear to suffer side effects.)

Himanshu Brahmbhatt, the director of EnGeneIC, who led the new study, says that as yet unpublished studies on 96 monkeys indicate that minicell treatment caused “only a minor immune response despite repeat dosing, and there is no sign of toxicity.” He says that his team will begin a safety trial, with minicells packed with anticancer drugs, on human subjects “within a couple of months.”

If subsequent safety tests of minicells containing RNA in dogs go as planned, then the twin treatment strategy of reversing drug resistance and then applying chemotherapy could be tested in people within 18 months, Brahmbhatt adds.